内质网膜蛋白编码基因seipin杂合性缺失对APP/PS1小鼠认知功能的影响  

The effects of loss of heterozygosity of seipin on cognitive function in APP/PS1 mice

作　　者：张子婷 黄鑫 曹静 贺子梅 石悦 陆利 杨静 Zhang Ziting;Huang Xin;Cao Jing;He Zimei;Shi Yue;Lu Li;Yang Jing(Department of Anatomy,Basic Medicine College,Shanxi Medical University,Taiyuan 030001,China)

机构地区：[1]山西医科大学基础医学院人体解剖学教研室,太原030001

出　　处：《神经解剖学杂志》2022年第5期514-522,共9页Chinese Journal of Neuroanatomy

基　　金：2021年山西省青年科学研究项目(202103022124561);2020年山西省高等学校教学改革创新项目(J2020094);山西省回国留学人员科研资助项目(2020-085)。

摘　　要：目的:探究内质网膜蛋白编码基因seipin杂合性缺失对APP/PS1小鼠认知功能的影响。方法:记录5月龄野生型(WT)、APP/PS1、seipin^(+/-)/APP/PS1小鼠体重和随机血糖,并进行腹腔葡萄糖耐量试验(IPGTT)和腹腔胰岛素耐量试验(IPITT)观察糖代谢的变化;运用Morris水迷宫(MWM)评估小鼠的认知能力;应用免疫组织化学法检测小鼠脑内β-淀粉样蛋白(Aβ)斑块沉积水平;通过Western Blot检测小鼠前额叶皮层胰岛素信号通路相关蛋白的变化;运用免疫荧光法检测小鼠前额叶皮层中Iba-1的表达并采用real time RT-PCR检测炎症相关因子的mRNA水平。结果:各组小鼠的体重和随机血糖无明显差异。seipin^(+/-)/APP/PS1组糖耐量曲线下面积(AUC)和胰岛素耐量AUC显著大于APP/PS1组(P<0.05)。MWM反向阶段seipin^(+/-)/APP/PS1组逃避潜伏期较APP/PS1和WT组显著增加,且在SE象限新平台的游程比、穿梭新平台所在位置次数均较APP/PS1和WT组显著降低(P<0.05)。同时我们还发现相较APP/PS1组,seipin^(+/-)/APP/PS1组前额叶皮层Aβ斑块数量显著增加(P<0.05),p-IRS1水平升高(P<0.05),p-Akt水平降低(P<0.05),且激活态小胶质细胞显著增多,iNOS、IL-1β、TNF-α和IL-6 mRNA表达显著增高(P<0.05)。结论:内质网膜蛋白seipin杂合性缺失可诱导APP/PS1小鼠早期外周糖代谢异常,从而影响前额叶皮层胰岛素代谢促使Aβ沉积,促进炎症因子表达,导致小鼠认知灵活性障碍。Objective:To explore the effects of heterozygosity loss of endoplasmic reticulum protein seipin on cognitive function of APP/PS1 mice.Methods:The body weight and the random blood glucose of five-month-old wild type(WT),APP/PS1 and seipin^(+/-)/APP/PS1 group were recorded,and glucose metabolism changes were detected by using intraperitoneal glucose tolerance test(IPGTT)and intraperitoneal insulin tolerance test(IPITT).The cognitive function was examined using the Morris water maze(MWM)test.The deposition of Aβplaque in brain was detected by immunohistochemistry.The changes of insulin signaling pathway related proteins in prefrontal cortex were detected by Western Blot.The expression of Iba-1 in prefrontal cortex was detected by immunofluorescence staining.The expressions of inflammatory-related cytokines in prefrontal cortex were detected by real time RT-PCR.Results:There were no significant differences in body weight and random blood glucose among all groups.The area under the glucose tolerance curve(AUC)and insulin tolerance AUC in seipin^(+/-)/APP/PS1 group were significantly higher than APP/PS1 group(P<0.05).MWM test showed that in the reverse phase,the escape latency of seipin^(+/-)/APP/PS1 group was significantly longer compared with APP/PS1 and WT group,and the number of times passing though the platform and the percentage of distance travelled in SE quadrant of seipin^(+/-)/APP/PS1 group was significantly shorter compared with APP/PS1 and WT group(P<0.05).Meanwhile,compared with APP/PS1 group,the number of Aβplaques significantly increased,p-IRS1 was significantly higher,p-Akt was lower,the number of amoebic morphology microglia significantly increased and more inflammatory cytokines IL-1β,iNOS,TNF-α,and IL-6 in the prefrontal cortex of seipin^(+/-)/APP/PS1 group(P<0.05).Conclusion:Loss of heterozygosity of endoplasmic reticulum protein seipin induces abnormal peripheral glucose metabolism in APP/PS1 mice,and upregulates inflammatory factors by influencing insulin metabolism in the prefrontal cortex th

关 键 词：seipin 阿尔茨海默病 胰岛素抵抗 炎症 认知 小鼠 

分 类 号：R749.16[医药卫生—神经病学与精神病学]